Application of mass spectrometry to facilitate advanced process controls of biopharmaceutical manufacture

Abstract

Development and implementation of process analytical technology and real-time release testing (here defined as advanced process controls) requires an approach to product development that emphasizes product and process understanding and process control, based on sound science and quality risk management (i.e., quality by design). Mathematical models can enhance the scientific understanding of a process and can also be explored for their predictive capability. Utilizing advanced process controls and mathematical models for biopharmaceutical products can be challenging given product/process complexity. Recent publications and preliminary work from our group are reviewed to show how the analytical capabilities of mass spectrometry can be leveraged to address these challenges. Advanced process controls as part of a control strategyProviding regulators with assurance of consistent product quality is a key component of a successful commercial filing. For biologics license applications (BLAs) submitted to the US FDA, regulations state (emphasis added), "Approval of a biologics license applica-tion…shall constitute a determination that the establishment(s) and the product meet applicable requirements to ensure the continued safety, purity, and potency of such products" [1]. To achieve this goal, both the applicant and the regulatory authority focus on the control strategy which is critical to providing consistent quality. As stated in the International Conference on Harmonisation Guidance for Industry Q8R2, "A control strategy is designed to ensure that a product of required quality will be produced consistently" [2]. Thus, the guidance and regulations align in the general intent that the manufacture of approved products will be controlled in a manner that ensures consistent quality.What constitutes an adequate control strategy? As defined in ICH Q10, a control strategy is a "…planned set of controls, derived from current product and process understanding, that assures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications and the associated methods and frequency of monitoring, and control" [3]. Conventional control strategies for biopharmaceuticals have, to date, used all of the elements listed in the Q10 definition. However, discussion about the appropriate blend of control elements is common during BLA and supplement review. ICH Q8 and Q11 have highlighted enhanced approaches using quality by design (QbD) concepts when developing a control strategy [2,4]. Under the QbD approach, testing, monitoring or controlling is shifted earlier into the process. QbD-related controls have included concepts like real-time release testing (RTRT; including use of models) [5] and process analytical tec hnology (PAT) [6].In this paper, a general overview of control strategies for biopharmaceutical products is provided and opportunities...

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