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CASSS Bay Area Discussion Group June 2017: Scientific Program
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Program Abstract

Impurities in biological drug products are typically classified as either product- or process‑related impurities. ICH Q6B defines process-related impurities as those that are derived from the manufacturing process, i.e. cell substrates, cell culture, or downstream processing, and exclude molecular variants of the product.  Examples of process-related impurities include: host cell proteins, DNA, media and buffer components, added oxidizing and/or reducing agents, inorganic salts and metals, and extractables/leachables from column resins, equipment, and containers. The majority of process-related impurities are almost entirely removed during the downstream purification process; however, residual levels of these agents may be left within the bulk drug substance and, subsequently, the drug product.

Global regulatory health authorities require that the control process-related impurities are addressed in regulatory dossiers, and that the risk to patient safety of residual amounts of process-related impurities be evaluated.   Expectations and the type of management of process-related impurities may vary, and typically evolve throughout the product lifecycle (beginning with first in human studies) of the product.

We will discuss strategies for evaluating process related impurities, assessing their risk and setting up appropriate control strategies to enable potential efficient and cost-effective development, production, and availability of safe and beneficial new products. 


Speaker Abstracts


A Regulatory Perspective on Characterization and Control of Process-Related Impurities - Click here to view presentation
Christopher Downey, CDER, FDA

The manufacture and testing process of biotechnology products must provide sufficient control process-related impurities and process contaminants. ICH Q6B broadly categorizes these impurities as cell substrate-derived, cell culture-derived, and downstream-derived. Process-related impurities or contaminants may pose a risk to patient safety or may affect the activity or stability of drug products. Consequently, these impurities need to be well controlled for the drug substance and drug product manufacturing processes and in some cases controlled with in-process or release tests. The control strategy for process-related impurities should be risk-based and will evolve over the course of clinical development and throughout post-approval lifecycle management. Dr. Downey will discuss regulatory experience and expectations related to control of these substances, including case studies. This will include not only discussions of the challenges of detecting and controlling host cell protein impurities, but will also provide examples of cell-culture and downstream-derived impurities.


Controlling Process-Related Impurities for Ocular Indications - Presentation Unavailable
Sara Parker, Genentech, a Member of the Roche Group

Control of process-related impurities in products intended for intravitreal administration requires special considerations compared to products intended for other routes of administration. This is due to the unique nature of the eye as well as minimal health authority guidance and publications on the subject. Here we present the risk assessment and control strategy for beta glucans as a case study for controlling process-related impurities in ocular drug products.


Impurities in Autologous Cell Therapies - Presentation Unavailable
Kanti Thirumoorthy, Kite Pharma, Inc.

Impurities in autologous cell therapies can be divided into two categories broadly. Those that are similar to other therapies – impurities like host cell protein, host cell DNA, upstream media components or processing aids. Then there are impurities from the subject’s apheresis material, a key raw material for the process. The challenges in the personalized subject raw material are unique to this therapy. We find the apheresis material to be highly variable depending on the type and disease stage of the subject, the types of previous treatments, and individual blood phenotype. The variability of this apheresis material from subject to subject plays an important role in critical quality attributes of the final product. The methods that can be typically used to assess these impurities are unique to the therapy. Measurement of live cells requires use of flow cytometry. Flow cytometry which employs use of staining of distinct cell surface markers and detection gets complicated when multiple cell types are being quantitated. Apheresis material, in-process and final product are characterized for B-cells, NK cells, different T cell phenotypes. Multiple gating strategies, complex analysis methods and lack of proper reference standards create challenges for qualification of the methods. Understanding the effect of any process changes and their results on these impurities and their decrease or clearance necessitate studying a huge number of lots due to the inherent variability already present in the starting material. The number of subjects in the studies, the accelerated pathways due to breakthrough designation and pivotal phase 2 followed by BLA makes the timelines of CMC activities very constrained. Establishing a characterization program in this therapy area creates challenges that the industry is trying to address in collaboration with regulatory agencies.





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